TOTAL SYNTHESIS OF STREPTOLYDIGIN AND RELATED SUBSTANCES

本研究建议概述了完成总的战略， 合成替兰达霉素B和利迪链菌素， 开发了一种合成替兰霉素A的方法。 替兰霉素 和利迪霉素是二烯酰基特特拉姆酸家族的成员， 从链霉菌的各种菌株中分离的抗生素。 已显示Streptolydigin选择性抑制末端 脱氧核苷酸转移酶（TDT），一种大量存在的酶 在白血病淋巴母细胞中，而不是在正常白细胞中。 TDT被认为是 在这些癌细胞的细胞代谢中起关键作用。 它 可能是，链霉菌素/替兰达霉素或这些天然的类似物 产品将被证明对各种白血病的治疗有效。 该提案还载有关于发展 螺缩酮和哌啶酮的合成方法。 使用此 方法，我们建议合成的螺缩酮部分的 驱虫化合物阿维菌素B1 b和B2b以及糖苷酶抑制剂 1-脱氧野尻霉素、N-甲基-1-脱氧野尻霉素和1-脱氧甘露野尻霉素。 糖苷酶抑制剂用于表征涉及的溶酶体酶 在糖蛋白的生物合成和加工中， 正常溶酶体代谢与溶酶体病的关系 states. 已知人溶酶体贮积病的每一种是 被这些物质抑制的糖苷酶及其研究 抑制活性将有助于理解异常代谢 与这些人类疾病有关。

This research proposal outlines strategies for the completion of the total synthesis of tirandamycin B and streptolydigin which is patterned after the approach developed for the synthesis of tirandamycin A. The tirandamycins and streptolydigin are members of the dienoyl tetramic acid family of antibiotics isolated from various strains of Streptomyces. Streptolydigin has been shown to selectively inhibit terminal deoxynucleotidyl transferase (TDT), an enzyme present in large quantities in leukemic lymphoblasts, but not in normal leucocytes. TDT is believed to play a crucial role in the cellular metabolism of these cancer cells. It is possible that streptolydigin/tirandamycin or an analog of these natural products will prove effective in the treatment of various leukemias. The proposal also contains sections concerning the development of methodology for the synthesis of spiroketals and piperidones. Using this methodology, we propose to synthesize the spiroketal moieties of the anthelmintic compounds avermectin B1b and B2b, and glycosidase inhibitors 1-deoxynojirimycin, N-methyl-1-deoxynojirimycin, and 1-deoxymannojirimycin. Glycosidase inhibitors are used to characterize lysosomal enzymes involved in the biosynthesis and processing of glycoproteins and to determine the relationship between normal lysomal metabolism and lysosomal disease states. A human lysosomal storage disease is known for each of the glycosidases which are inhibited by these substances and study of their inhibitory activity will aid in understanding the aberrant metabolism associated with these human disorders.